Matrix metalloprotease (MMPs) are calcium dependent, zinc containing enzymes that degrade a wide range of extracellular proteins as well as process bioactive molecules into an active form. In humans, there are over two dozen known MMPs and these are conserved through many vertebrate animals and have also been found in invertebrates and plants. These include MMP-1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23A, 23B, 24, 25, 26, 27, and 28. Under normal physiological conditions, MMP activity is precisely controlled—such as through tissue inhibitors of MMPs (TIMPs)—to maintain a low level of structural protein, cell receptor, and growth factor turnover. However, under pathophysiological conditions, there is a persistence of MMP activity that causes maladaptive changes to tissue architectures and functions, contributing to disease progression.
Excessive extracellular matrix (ECM) proteolysis by MMPs is a hallmark of many human disease states including chronic inflammation, tumour progression and cardiovascular disease. The induction of MMPs has been shown to play a role in abdominal, thoracic and aortic aneurysms, multiple forms of cancer, rheumatoid arthritis, osteoarthritis, restenosis, myocardial infarction, stroke, rosacea, eye disease, chronic obstructive pulmonary disease, psoriasis, macular degeneration, multiple sclerosis, myocardial rupture, left ventricular hypertrophy, and Kaposi's sarcoma.
In order to treat these indications, the design and development of molecules that inhibit MMP activity has been a widely explored area of research over the past 25 years. These molecules include those based on hydroxymates and non-hydroxymate chemistries including thiol, phosphinyl, tetracycline, mercaptoalkylpeptidyl, 6,7-dihydroxy-coumarin, carboxylate, and bis-sulfonamide. Further novel inhibitors including peptide sequences, and molecules derived from shark cartilage extract have been developed. Unfortunately none of these MMP inhibitors have been translated to clinical application owing to the dose-limiting side effects following systemic administration of these molecules. While many of these molecules are potent inhibitors of MMPs, they do so through non-specific interactions such as catalytic zinc ion chelation or binding to the side pocket of the enzyme. Further, all MMPs share significant sequence and structural homology. As a result, these inhibitors have poor selectivity for specific MMP enzymes which may be implicated in a targeted disease, and therefore have off-target effects when delivered systemically due to broad spectrum MMP inhibition throughout the body. For example, muscloskeletal syndrome or pain and stiffness in the joints was commonly reported during clinical trials where MMP inhibitors were delivered systemically to treat myocardial infarction in patients.
To limit off-target effects of therapeutics, biomaterials—including injectable and water-swollen polymer networks or hydrogels—have acted as depots to locally deliver therapeutics through diffusion and degradation mechanisms. Typically, these material systems are engineered to achieve a release profile to adequately dose patients within a therapeutic window specific to a disease. However, the absolute magnitude and temporal variation of MMP activity in patients is highly variable; therefore, one hydrogel formulation and inhibitor dose may not be widely applicable across patient populations.
The present invention described in this patent application address these concerns of broad spectrum MMP inhibitors by encapsulating them in an injectable hydrogel technology that targets delivery of the inhibitors to a diseased tissue and releases the inhibitors in response to elevated MMP activity. Importantly, the inhibitors are sequestered in the hydrogel through non-covalent interactions including hydrophobic, electrostatic, Van der Walls, and polarization forces. MMP specificity can be designed into the hydrogel by engineering the sequence of the MMP degradable crosslinker. Further, the physical properties of the hydrogel can be controlled to ensure localization in a wide range of diseased tissues where elevated MMP activity contributes to disease progression.
Cardiac problems are a major global health concern. According to the American Heart Association, 1.26 million people suffer from heart attacks annually. If the patient survives, they are at a high risk for developing heart failure. Left ventricular remodeling contributes to heart failure, which in 1995, affected 2 million people (Schocken et al, J Am Coll Cardiol. 1992 August; 20 (2):301-6). The incidence and death by heart failure has been steadily increasing for years, suggesting that the potential patient population may continue to grow significantly over time. Many therapeutic approaches, both pharmacologic and surgical, have been developed to treat heart failure. Most therapies are directed at patients who have already developed symptoms. Few if any are directed at patients in the early post myocardial infarction time period before symptoms develop. None are directed at limiting extracellular matrix destruction by matrix metalloprotease. Typically, a patient suffering a heart attack is given a cocktail of medicines that can be difficult to titrate and manage. Efficacy is often not achieved. The population of heart failure patients continues to grow in spite of the current therapeutic armamentarium.
In a paper published in Circulation (June 2003, p 2857), Wilson et al determined that certain matrix metalloprotease (MMP), such as MMP-13 are upregulated post-MI, perhaps resulting in the left ventricular remodeling that adversely affects heart function. Further, they found that the antagonist to MMP-13, TIMP, is down-regulated. In particular, this study demonstrated increased levels of MMP-13 and MT1-MMP after MI, which may have particular significance with respect to pathological remodeling. Specifically, MMP-13 is increased in end-stage cardiomyopathies and aggressive breast carcinomas. MMP-13 degrades fibrillar collagens and therefore may contribute to myocardial extracellular remodeling. Increased MT1-MMP levels within the transition and MI regions may have particular significance, for two reasons. First, MT1-MMP degrades a wide range of extracellular matrix proteins. Second, MT1-MMP can proteolytically process soluble pro-MMPs, such as pro-MMP-13,2 and thereby amplify local proteolytic activity. The LV regions in which this local induction of MT1-MMP and MMP-13 occurred were paralleled by decreased TIMP levels. The present study demonstrated that increased MT1-MMP levels and decreased TIMP-4 levels were correlated to the extent of regional LV remodeling. This regional imbalance between these specific MMPs and TIMPs probably contributed to continued regional expansion in the post-MI myocardium.
There is a need in the art for treatments to minimize left ventricular remodeling associated with MI. In addition to LV remodeling uses, there is also a need in the art to provide regional delivery of MMP inhibiting therapy that would be active only where MMP's are active.